Abstract

T-type calcium channels (CaV3) play an important role in many physiological and pathological processes, including cancerogenesis. CaV3 channel blockers have been proposed as potential cancer treatments. Roscovitine, a trisubstituted purine, is a cyclin-dependent kinase (CDK) inhibitor that is currently undergoing phase II clinical trials as an anticancer drug and has been shown to affect calcium and potassium channel activity. Here, we investigate the effect of roscovitine on CaV3.1 channels. CaV3.1 channels were transiently expressed in human embryonic kidney 293 cells, and currents were recorded by using the whole-cell patch-clamp technique. Roscovitine blocks CaV3.1 channels with higher affinity for depolarized cells (EC50 of 10 μM), which is associated with a negative shift in the voltage dependence of closed-state inactivation. Enhanced inactivation is mediated by roscovitine-induced acceleration of closed-state inactivation and slowed recovery from inactivation. Small effects of roscovitine were also observed on T-channel deactivation and open-state inactivation, but neither could explain the inhibitory effect. Roscovitine inhibits CaV3.1 channels within the therapeutic range (10–50 μM) in part by stabilizing the closed-inactivated state. The ability of roscovitine to block multiple mediators of proliferation, including CDKs and CaV3.1 channels, may facilitate its anticancer properties.

Footnotes

This work was supported in part by grants from the Pennsylvania Department of Health using Tobacco Settlement Funds; and the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant AR059397].